Amino-esters of dihydropyridines, and their use as circulatory agents for treating ischaemic heart diseases

ABSTRACT

Circulation active compounds of the formula ##STR1## in which R 1  is phenyl or heterocyclyl substituted by nitro, trifluoromethyl or other radicals, 
     R 2  is optionally substituted alkyl or other radical 
     R 3  and R 5  are hydrogen, methyl or other radicals, 
     R 4  is hydrogen or optionally substituted alkyl, 
     X is from 2 to 15, and 
     R 6  is ##STR2## and physiologically acceptable salts thereof.

This is a division of now pending application Ser. No. 07/018,652, filedFeb. 25, 1987, now U.S. Pat. No. 4,861,782.

The invention relates to amino-esters of dihydropyridines, processes forpreparation and their use as medicaments, in particular as medicamentswhich influence the circulation.

It is known that diethyl1,4-dihydro-2,6-dimethyl4-phenyl-pyridine-3,5-dicarboxylate is obtainedwhen ethyl 2-benzylideneacetoacetate is reacted with β-aminocrotonicacid ester or ethyl acetoacetate with ammonia [E. Knoevenagel, Ber.dtsch. Chem. Ges. 31, 743 (1898)].

It is also known that certain 1,4-dihydropyridines have interestingpharmacological properties [F. Bossert, W. Vater, Naturwissenschaften58, 578 (1971)].

The present invention relates to new amino-ester dihydropyridines of thegeneral formula (I) ##STR3## in which R¹ represents C₆ -C₁₄ -aryl, orrepresents heterocyclyl from the series comprising thienyl, furyl,pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl,pyridazinyl, pyrimidyl, pyrazinyl, indolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiadiazolyl,quinolyl, isoquinolyl, quinazolyl or quinoxalyl, it being possible forthe ring systems mentioned in each case to be substituted by one or twoidentical or different substituents from the group comprising phenyl,straight-chain or branched C₁ -C₄ -alkyl, C₃ -C₇ -cycloalkyl, C₁ -C₄-alkoxy, C₁ -C₄ -alkylthio, tri-, tetra- or pentamethylene,dioxymethylene, dioxyethylene, halogen, trifluoromethyl,trifluoromethoxy, difluoromethoxy, tetrafluoroethoxy, nitro, cyano andazido,

R² represents a straight-chain, branched or cyclic, saturated orunsaturated hydrocarbon radical which has up to 15 carbon atoms, isoptionally interrupted in the chain by an oxygen atom or a sulphur atomand/or is optionally substituted by halogen, cyano, hydroxyl, C₂ -C₇-acyloxy, nitro or nitrooxy or by a phenyl, phenoxy, phenylthio orphenylsulphonyl group, which is in turn optionally substituted by di-C₁-C₂ -alkylamino, C₁ -C₄ -alkoxy, C₁ -C₄ -alkyl, halogen, trifluoromethylor nitro, or by an α-, β- or γ-pyridyl group, or by an amino group, thisamino group carrying two identical or different substituents from thegroup comprising C₁ -C₄ -alkyl, C₁ -C₆ -alkoxyalkyl, phenyl and benzyl,or the substituents optionally forming, with the nitrogen atom, a 5- to7-membered ring which can contain, as a further hetero atom, an oxygenor sulphur atom or an N-phenyl or N-alkyl grouping, the alkyl groupcomprising one to three carbon atoms,

R³ and R⁵ are identical or different and in each case representhydrogen, a straight-chain, branched or cyclic alkyl radical with up to8 carbon atoms or a phenyl or benzyl radical, or one of the substituentsR³ or R⁵ represents an alkyl radical with up to 6 carbon atoms, which issubstituted by acetoxy, benzoyloxy, C₁ -C₃ -alkoxy, C₁ -C₃ -dialkoxy,hydroxyl, amino, C₁ -C₆ -amino alkoxy, phthalimido, C₁ -C₆-phthalimidoalkoxy, C₁ -C₆ -piperidinoalkoxy, C₁ -C₆ -morpholinoalkoxyor N-phenyl-N'-piperazinoalkoxy with up to 6 carbon atoms, or representsformyl or nitrile,

R⁴ represents hydrogen, or represents a straight-chain or branched alkylradical which has up to four carbon atoms, is optionally interrupted inthe chain by an oxygen atom and/or is optionally substituted by apiperidino or morpholino radical, or represents phenyl or benzyl,

X represents a number from 2 to 15 and

R⁶ represents a radical of the formula ##STR4## wherein R⁷ representshydrogen or methoxy and

R⁸ represents hydrogen, or represents straight-chain or branched C₁ -C₆-alkyl, or represents the group of the formula ##STR5## andphysiologically acceptable salts thereof.

Preferred compounds of the formula (I) are those in which

R¹ represents phenyl, thienyl, furyl, pyridyl, quinolyl orbenzoxadiazolyl, the ring systems mentioned optionally being substitutedby one or two identical or different substituents from the groupcomprising phenyl, C₁ -C₂ -alkyl, C₁ -C₂ -alkoxy, C₁ -C₂ -alkylthio,dioxymethylene, fluorine, chlorine, bromine and iodine, trifluoromethyl,trifluoromethoxy, difluoromethoxy, nitro and cyano,

R² represents a straight-chain, branched or cyclic, saturated orunsaturated hydrocarbon radical which has up to 10 carbon atoms and isoptionally interrupted in the chain by an oxygen atom and/or isoptionally substituted by fluorine, chlorine, bromine, iodine, cyano,acetoxy or hydroxyl, or by a phenyl or phenoxy group which is optionallysubstituted by fluorine, chlorine, C₁ -C₂ -alkyl, C₁ -C₂ -alkoxy ortrifluoromethyl, or by an α- or β- or γ-pyridyl group, or by a tertiaryamino group, this amino group carrying two identical or differentsubstituents from the group comprising C₁ -C₄ -alkyl, phenyl and benzyl,

R³ and R⁵ are identical or different and in each case represent astraight-chain, branched or cyclic alkyl radical with up to 6 carbonatoms, or one of the substituents R³ or R⁵ represents an alkyl radicalwhich has up to 4 carbon atoms and is substituted by acetoxy, methoxy,dimethoxy, hydroxyl, amino, phthalimido, aminoalkoxy orphthalimidoalkoxy with in each case up to 4 carbon atoms per alkoxygroup, or represents formyl or cyano,

R⁴ represents hydrogen or represents a straight-chain or branched alkylradical which has up to four carbon atoms, is optionally interrupted inthe chain by an oxygen atom and/or is optionally substituted by apiperidino or morpholino radical or represents benzyl,

X represents a number of 2 to 10, and

R⁶ represents a radical of the formula ##STR6## wherein R⁷ representshydrogen or methoxy and

R⁸ represents hydrogen, or represents straight-chain or branched C₁ -C₄-alkyl, or represents the radical of the formula ##STR7## and theirphysiologically acceptable salts.

Particularly preferred compounds of the general formula (I) are those inwhich

R¹ represents phenyl, pyridyl or benzoxadiazolyl, the phenyl ring beingsubstituted by 1 or 2 identical or different substituents from the groupcomprising chlorine, trifluoromethyl, nitro and cyano,

R² represents a straight-chain or branched hydrocarbon radical which hasup to 7 carbon atoms and is optionally interrupted in the chain by anoxygen atom and/or is optionally substituted by fluorine, cyano, phenylor α-, β- or γ-pyridyl or by N-benzyl-N-methylamino,

R³ and R⁵ represent methyl,

R⁴ represents hydrogen,

X represents a number from 2 to 6 and

R⁶ represents a radical of the formula ##STR8## wherein R⁷ representshydrogen or methoxy and

R⁸ represents hydrogen, or represents straight-chain or branched C₁ -C₄-alkyl, or represents the radical of the formula ##STR9## and theirphysiologically acceptable salts.

Physiologically acceptable salts are salts of the compounds according tothe invention with inorganic or organic acids. These include,preferably, inorganic acids, such as hydrogen halide acids, preferablyHCl or HBr, sulphuric acid or phosphoric acid, or organic carboxylicacids or sulphonic acids, such as, for example, acetic acid, maleicacid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid,benzoic acid, methanesulphonic acid, ethanesulphonic acid,benzenesulphonic acid, naphthalenedisulphonic acid or toluenesulphonicacid.

The compounds according to the invention exist in stereoisomeric formswhich either behave as mirror images (enantiomers) or do not behave asmirror images (diastereomers). The invention relates both to theantipodes and to the racemic forms as well as diastereomeric mixtures.The racemic forms, like the diastereomers, can be resolved into thestereoisomerically uniform constituencs in a known manner (E. Eliel,Stereochemistry Of Carbon Compounds McGraw Hill, 1962).

The amino-esters of dihydropyridines of the general formula (I)according to the invention are prepared by a process in which compoundsof the general formula (II) ##STR10## in which R¹ -R⁵ and X have theabovementioned meaning and

A represents halogen or the radical NHR⁸ wherein

R⁸ has the abovementioned meaning are reacted with compounds of theformula (III)

    B--R.sup.6                                                 (III)

in which

R⁶ has the abovementioned meaning and

B represents a reactive radical from the group comprising halogen,carbonyl and a secondary amino group,

in inert organic solvents at temperatures from 0° to 200° C. and, ifstarting compounds of the formula (III) with reactive carbonyl groupsare used, the resulting Schiff's bases are reduced by customary methods.

The following preferred embodiments of the process according to theinvention may be mentioned as preferred process variants for certainsubstituents of the compounds of the general formula (I) according tothe invention:

(A) The compounds of the general formula (Ia) according to the invention##STR11## in which

R¹ -R⁵, R⁸ and X have the meaning given, are obtained by a process inwhich amino compounds of the general formula (IIa) ##STR12## in which

R¹ -R⁵, X and R⁸ have the meaning given, are reacted with halogencompounds of the general formula (IIIa) ##STR13## in which

Hal represents fluorine, chlorine, bromine or iodine, preferablychlorine or bromine, in inert organic solvents, if appropriate in thepresence of a base, if appropriate the products are then alkylated, andif appropriate the physiologically acceptable salts are prepared withacids.

Depending on the nature of the starting compounds used, the processaccording to the invention can be illustrated by the following equation:##STR14##

The amino compounds (IIa) employed as starting substances are known orcan be prepared by known methods [U.S. Pat. No. 3,985,758; European Pat.No. 151,006].

The halogen compounds of the formula (IIIa) used as starting substancesare known or can be prepared by known methods [Biochem. Pharmacol.,30(12), 1685-92].

Solvents which can be used are the customary organic solvents which donot change under the reaction conditions. These include, preferably,alcohols, such as methanol, ethanol, propanol and isopropanol, ethers,such as diethyl ether, dioxane or tetrahydrofuran, dimethylformamide,dimethylsulphoxide, acetonitrile, ethyl acetate, hexamethylphosphoricacid triamide, pyridine, picoline, N-methylpiperidine and hydrocarbons,such as benzene, toluene or xylene. Mixtures of the solvents mentionedcan likewise be employed.

Suitable bases are the customary inorganic or organic bases. Theseinclude, preferably, alkali metal hydroxides, such as sodium orpotassium hydroxide, alkali metal carbonates, such as sodium orpotassium carbonates, alkali metal alcoholates, such as sodium orpotassium methanolate or sodium or potassium ethanolate, or organicamines, such as trialkylamines, for example triethylamine, pyridine,picoline or N-methylpiperidine, or amides, such as sodium amide orlithium diisopropylamide, or metal-organyls, such as, for example,butyl-lithium or phenyllithium.

The reaction is in general carried out in a temperature range from 0° C.to 200° C., preferably from room temperature up to the boiling point ofthe particular solvent.

The reaction is in general carried out under normal pressure. However,it is also possible to carry out the reaction under increased or reducedpressure.

For the synthesis of the compounds of the formula (Ia) in which R⁸represents hydrogen or C₁ -C₆ -alkyl, the corresponding amino compoundsof the formula (IIa) are preferably employed in molar to twice the molaramounts. For the synthesis of the compounds of the formula (Ia) in whichR⁸ represents the group of the formula ##STR15## the correspondinghalogen compound of the formula (IIIa) is preferably employed in twiceto three times the molar amounts.

The base is employed in an amount of 1 to 100 mol, preferably 1 to 50mol, per mol of amino compound.

If appropriate, subsequent alkylation is carried out by methods whichare known per se, in inert solvents, such as alcohols, for examplemethanol, ethanol or n- or i-propanol, ethers, for example diethylether, dioxane or tetrahydrofuran, or halogenohydrocarbons, such asmethylene chloride, chloroform or carbon tetrachloride, or hydrocarbons,such as benzene, toluene, xylene or hexane, with alkylating agents suchas alkyl halides, preferably alkyl bromides or alkyl iodides, dialkylsulphates or diazoalkanes, if appropriate with bases, such as NaOH, KOHor sodium or potassium hydroxide or organic bases, such as triethylamineor pyridine, as is described in detail, for example, in "Organikum",11th edition, VFB Deutscher Verlag der Wissenschaften Berlin 1972, page228.

(B) The compounds of the general formula (Ib) ##STR16## in which

R¹ -R⁵, R⁷ and X have the meaning given, are prepared by a process inwhich, in a first step, ketones of the formula (IIIb) ##STR17## arereacted with amines of the formula (IIa) in which

R¹ -R⁵, R⁷ and X have the meaning given and

R⁸ represents hydrogen,

in an inert organic solvent, if appropriate in the presence of acatalyst, the Schiff's bases thus obtained are reduced in inert solventsin a second step and, if appropriate, the pharmacologically acceptablesalts are then prepared with acids.

If 3-(2-aminoethyl) 5-methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylateand 1,3,4,6,7,11b-hexahydro-8,9-dimethoxy-2-oxo-2H-benzo[a]-quinolizineof the formula (IIb) are used as starting substances, the synthesis ofthe compounds of the formula (Ib) according to the invention can beillustrated by the following equation: ##STR18##

The ketones of the formula (IIIb) used as the starting material are new.They can be prepared by known methods, such as is described, forexample, by D. Beke and C. Szantay in Chem. Ber. 95, 2132 (1962).

The compounds of the general formula (IIa) used as starting substancesare known or can be prepared by known methods [U.S. Pat. No. 3,985,758;European Pat. No. 151,006].

The preparation of the Schiff's bases in the first step is carried outin a manner which is known per se in inert organic solvents, ifappropriate in the presence of a catalyst and if appropriate in thepresence of a water-binding agent. The process according to theinvention can be carried out in two steps, that is to say with isolationof the Schiff's bases. It is also possible to carry out the reaction asa one-pot process.

Suitable diluents here are the customary organic solvents which are notchanged under the reaction conditions. These include, preferably,alcohols, such as methanol, ethanol, propanol or isopropanol, ethers,such as diethyl ether, dioxane or tetrahydrofuran, halogenohydrocarbons,such as, for example, methylene chloride, chloroform or carbontetrachloride, dimethylformamide or aromatic hydrocarbons, such as, forexample, benzene, toluene or xylene. It is also possible to use mixturesof the solvents mentioned.

Acids are in general used as catalysts. These include, preferably,inorganic acids, such as, for example, hydrochloric acid or sulphuricacid, or organic acids, such as, for example, methane-, ethane-,benzene- or toluenesulphonic acid, or acetic acid. It is also possibleto use acetic acid as a mixture with acetic anhydride as a dehydratingagent. The water formed during the reaction can be removed, ifappropriate as a mixture with the solvent used, during or after thereaction, for example by distillation, or by addition of water-bindingagents, such as, for example, phosphorus pentoxide, or preferably by amolecular sieve.

The reaction is in general carried out at a temperature in the rangefrom 0° C. to 150° C., preferably from 20° C. up to the boiling point ofthe particular solvent.

The reaction can be carried out under normal, increased or reducedpressure. It is in general carried out under normal pressure.

In carrying out the reaction, the starting substances are in generalemployed in a molar ratio of ketone IIIb to amine (IIa) of 0.5:2 to 1:2.Molar amounts of the reactants are preferably used.

The procedure for the preparation of the Schiff's bases from the ketoneIIIb and amine (IIa) is not restricted to the variants described, butcan also be carried out by other known methods, which are described, forexample, in Houben-Weyl "Methoden der organischen Chemie" ("Methods ofOrganic Chemistry"), Volume 11/2.

The reduction of the Schiff's bases to give the compounds of the formula(Ib) according to the invention is carried out by customary methods,either by hydrogen in inert organic solvents, such as alcohols, ethersor halogenohydrocarbons, with catalysts, such as Raney nickel,palladium, palladium-on-animal charcoal or platinum, or with hydrides ininert organic solvents, if appropriate in the presence of a catalyst.

The reaction is preferably carried out with hydrides, such as complexalkali metal borohydrides or aluminium hydrides. Sodium borohydride,lithium aluminium hydride or cyanoborohydride are preferably employedhere.

Suitable solvents here are all the inert organic solvents which do notchange under the reaction conditions. These include, preferably,alcohols, such as methanol, ethanol, propanol or isopropanol, ethers,such as diethyl ether, dioxane or tetrahydrofuran, or dimethylformamide.

Acids are in general used as catalysts. These include, preferably,inorganic acids, such as hydrochloric acid or sulphuric acid, or organicacids, such as carboxylic acids or sulphonic acids, for example aceticacid, trifluoroacetic acid or methane-, ethane-, benzene- ortoluenesulphonic acid.

(C) The compounds of the general formula (Ic) according to the invention##STR19## in which

R¹ -R⁵ and X have the meaning given,

are obtained by a process in which

[1]Amino-dihydropyridines of the general formula (IIa) ##STR20## inwhich

R¹ -R⁵ and X have the meaning given,

are reacted with halogen compounds of the formula (IIIc) ##STR21## inwhich

Hal represents fluorine, chlorine, bromine or iodine, preferablychlorine or bromine, in inert organic solvents, if appropriate in thepresence of a base, and, if appropriate, the physiologically acceptablesalts are prepared with acids, or by a process in which

[2]Amino-dihydropyridines of the formula (IIa) are reacted with carbonylcompounds of the formula (IIIcc) ##STR22## in an inert solvent, ifappropriate in the presence of a catalyst, the Schiff's bases thusobtained are reduced in inert solvents in a second step and, ifappropriate, the physiologically acceptable salts are then prepared withacids.

Depending on the nature of the starting substances used, processes C1and C2 can be illustrated by the following equation: ##STR23##

The amino-dihydropyridines (IIa) employed as starting substances areknown or can be prepared by known methods [U.S. Pat. No. 3,985,758;European Pat. No. 151,006].

The halogen compounds (IIIc) employed as starting substances are knownor can be prepared by known methods [DE-OS (German PublishedSpecification) No. 3,124,366].

The carbonyl compound of the formula (IIIcc) employed as the startingsubstance is known [Petragnani et al., Il Farmaco -Ed.Sc.-vol.32-fasc.7,512] .

Suitable solvents for process C1 are the customary organic solventswhich do not change under the reaction conditions. These include,preferably, alcohols, such as methanol, ethanol, propanol andisopropanol, ethers, such as diethyl ether, dioxane or tetrahydrofuran,dimethylformamide, dimethylsulphoxide, acetonitrile, ethyl acetate,hexamethylphosphoric acid triamide, pyridine, picoline,N-methylpiperidine or hydrocarbons, such as benzene, toluene or xylene.It is also possible to employ mixtures of the solvents mentioned.

Suitable bases for process C₁ are the customary inorganic or organicbases. These include, preferably, alkali metal hydroxides, such assodium hydroxide or potassium hydroxide, alkali metal carbonates, suchas sodium carbonate or potassium carbonate, alkali metal alcoholates,such as sodium methanolate or potassium methanolate, sodium ethanolateor potassium ethanolate or potassium tert.-butanolate, or organicamines, such as trialkylamines, for example triethylamine, pyridine,picoline or N-methylpiperidine, or amides, such as sodium amide orlithium diisopropylamide, or metal-organyls, such as, for example,butyl-lithium or phenyl-lithium.

The reaction is in general carried out in a temperature range from 0° C.to 200° C., preferably from room temperature up to the boiling point ofthe particular solvent.

The reaction is in general carried out under normal pressure. However,it is also possible to carry out the reaction under increased or reducedpressure.

In general 0.5 to 5 mol, preferably 1 to 2 mol, of halogen compound(IIIc) and 1 to 100, preferably 1 to 50, mol of base are employed in thereaction per mol of amino compound (IIa).

The preparation of the Schiff's bases in the first step of process C₂ iscarried out in a manner which is known per se in inert organic solvents,if appropriate in the presence of a catalyst and if appropriate in thepresence of a water-binding agent. The process according to theinvention can be carried out in two steps, that is to say with isolationof the Schiff's bases. It is also possible to carry out the reduction asa one-pot process.

Suitable diluents here are the customary organic solvents which are notchanged under the reaction conditions. These include, preferably,alcohols, such as methanol, ethanol, propanol or isopropanol, ethers,such as diethyl ether, dioxane or tetrahydrofuran, halogenohydrocarbons,such as, for example, methylene chloride, chloroform or carbontetrachloride, dimethylformamide or aromatic hydrocarbons, such as, forexample, benzene, toluene or xylene. It is also possible to use mixturesof the solvents mentioned.

Acids are in general used as catalysts. These include, preferably,inorganic acids, such as, for example, hydrochloric acid or sulphuricacid, or organic acids, such as, for example, methane-, ethane-,benzene- or toluenesulphonic acid, or acetic acid. It is also possibleto use acetic acid as a mixture with acetic anhydride as a dehydratingagent. The water formed during the reaction can be removed, ifappropriate as a mixture with the solvent used, during or after thereaction, for example by distillation, or by addition of water-bindingagents, such as, for example, phosphorus pentoxide, or preferably by amolecular sieve.

The reaction is in general carried out at a temperature in the rangefrom 0° C. to 150° C., preferably from 20° C. up to the boiling point ofthe particular solvent.

The reaction can be carried out under normal, increased or reducedpressure. It is in general carried out under normal pressure.

In carrying out the reaction, the starting substances are in generalemployed in a molar ratio of carbonyl compound (IIIcc) to amine (IIa) of0.5:2 to 1:2. Molar amounts of the reactants are preferably used.

The procedure for the preparation of the Schiff's bases from thecarbonyl compound (IIIcc) and amines (IIa) is not restricted to thevariants described, but can also be carried out by other known methods,which are described, for example, in Houben-Weyl "Methoden derorganischen Chemie" ("Methods of Organic Chemistry"), Volume 11/2.

The reduction of the Schiff's bases to give the compounds of the formula(Ic) according to the invention is carried out by customary methods,either by hydrogen in inert organic solvents, such as alcohols, ethersor halogenohydrocarbons, with catalysts, such as Raney nickel,palladium, palladium-on-animal charcoal or platinum, or with hydrides ininert organic solvents, if appropriate in the presence of a catalyst.

The reaction is preferably carried out with hydrides, such as complexalkali metal borohydrides or aluminium hydrides. Sodium borohydride,lithium aluminium hydride or cyanoborohydride are preferably employedhere.

Suitable solvents here are all the inert organic solvents which do notchange under the reaction conditions. These include, preferably,alcohols, such as methanol, ethanol, propanol or isopropanol, ethers,such as diethyl ether, dioxane or tetrahydrofuran, or dimethylformamide.

Acids are in general used as catalysts. These include, preferably,inorganic acids, such as hydrochloric acid or sulphuric acid, or organicacids, such as carboxylic acids or sulphonic acids, for example aceticacid, trifluoroacetic acid or methane-, ethane-, benzene- ortoluenesulphonic acid.

(D) The compounds of the general formula (Id) according to the invention##STR24## in which

R¹ -R⁵ and X have the meaning given, are obtained by a process in whichdihydropyridine halogeno-esters of the general formula (IId) ##STR25##in which

R¹ -R⁵ and X have the meaning given and Hal represents fluorine,chlorine, bromine or iodine, preferably chlorine or bromine,

are reacted with the imidazole of the formula (IIId) ##STR26## in inertorganic solvents, if appropriate in the presence of a base.

The preparation of the compounds of the formula (Id) according to theinvention can be illustrated by the following equation: ##STR27##

The dihydropyridine halogeno-esters (IId) employed as startingsubstances are known or can be prepared by known methods [Kuthan et al.,Ind. Eng. Chem. Prod. Res. Der. 21, 191 (1982)].

The imidazole (IIId) employed as the starting substance is known or canbe prepared by known methods [U.S. Pat. No. 4,302,469].

Suitable solvents are the customary organic solvents which do not changeunder the reaction conditions. These include, preferably, ethers, suchas diethyl ether, dioxane, tetrahydrofuran or glycol mono- or dimethylether, amides, such as dimethylformamide or hexamethylphosphoric acidtriamide, halogenohydrocarbons, such as methylene chloride, chloroformor carbon tetrachloride, hydrocarbons, such as benzene, toluene orxylene, alcohols, such as methanol, ethanol, propanol or isopropanol, orbases, such as pyridine, picoline, or N-methylpiperidine. Mixtures ofthe solvents mentioned can also be used.

Suitable bases are the customary inorganic or organic bases, such assodium or potassium, alkali metal hydrides, such as sodium hydride orpotassium hydride, alkali metal amides, such as sodium amide or lithiumdi-isopropylamide, organolithium compounds, such as butyl-lithium orphenyl-lithium, alkali metal alcoholates, such as potassium methanolateor ethanolate, sodium methanolate or ethanolate or potassiumtert.-butanolate, alkali metal hydroxides, such as sodium hydroxide orpotassium hydroxide, or alkali metal carbonates, such as sodiumcarbonate or potassium carbonate, or organic amines, such astrialkylamines, for example triethylamine, pyridine,1,5-diazabicyclo(4,3,0)non-5-ene or 1,5-diazabicyclo(5,4,0)undec-5-ene.

The reaction is in general carried out in a temperature range from -20°to 100° C., preferably from 0° C. to 80° C. The reaction can be carriedout under normal pressure, but also under increased or reduced pressure.It is in general carried out under normal pressure.

In carrying out the reaction, in general 0.5 to 5 mol, preferably 1 to1.5 mol, of dihydropyridine halogenoester (IId) and 1 to 50, preferably1 to 10, mol of base are employed per mol of imidazole (IIId).

The compounds according to the invention are suitable as therapeuticsfor the treatment of ischaemic heart disease and essential hypertension.

In the therapy of ischaemic heart diseases (various clinical forms ofangina pectoris, cardiac infarction and cardiac failure), they have apositive influence on the fundamental pathogenetic mechanisms, chieflythe restricted availability of oxygen.

In addition to the calcium-antagonistic activity, the compoundsaccording to the invention also exhibit an antagonizing effect onvascular alpha-adrenoreceptors (alpha-blockade). The therapeutic actionspectrum of these substances is accordingly supplemented by venouspooling and a myocardial-preserving reduction in the preload. Thisimproves the therapeutic efficacy and enables a larger number ofpatients to be treated therapeutically.

The compounds according to the invention also exhibit the same positiveaction in the treatment of hypertension. Due to the additional reductionin the preload on the heart, hypertensive patients with hyperdynamiccirculatory regulation, only some of whom can be treated withconventional products, are also successfully treated. The vein-dilatingheart-relieving therapy also leads in hypertensive patients to areduction in cardiac hypertrophy, an improvement in cardiac output incases of cardiac insufficiency and a reduction in the oxygen requirementof seriously ill hypertensive patients. The therapeutic possibilitiesfor these chronic, widespread circulatory diseases are thus considerablyimproved.

The specific calcium-antagonistic action of the compounds according tothe invention is examined in a test on isolated rabbit vessels (aorta).In this test, contractions of the vascular muscle are caused in vitro bystimulation with KCl or by noradrenaline. KCl causes contractions due tothe depolarization-dependent inwards flow of calcium ions.

These contractions are inhibited by calcium-antagonistic drugs as afunction of the dose. Noradrenaline causes contractions by stimulationof the vascular alpha-receptors and the resulting release of calciumions from the intracellular stores. The noradrenaline-inducedcontractions are not inhibited by specific calcium antagonists. Incontrast, antagonists of the alpha-adrenoreceptors inhibit only thenoradrenaline-induced contraction.

Surprisingly, the compounds according to the invention inhibit bothdepolarization (KCl)-induced and noradrenaline-induced contractions ofthe isolated vascular muscle of rabbits (see Table 1).

The vein volume of an extremity is measured by plethysmography onanaesthetized cats (ketamine). The arterial blood pressure is alsorecorded at the same time. Calcium-antagonistic DHP derivatives knownhitherto reduce the arterial blood pressure and reduce the vein volumeby reflectory vein constriction. Antagonists of adrenergicalpha-receptors, such as phentolamine, prazosin or yohimbine, lead to anincrease in the vein volume by reduction of the adrenergic venous tone.

The compounds according to the invention reduce the arterial bloodpressure and simultaneously increase the vein volume, and thereby causevenous pooling in addition to arterial vasodilation (see Table 2).

The compounds according to the invention are also active after oraladministration. The arterial blood pressure of conscious rats withhypertension of genetic origin ("spontaneously hypertensive rats" of theOkamoto strain) is measured bloodlessly with a "tail cuff" at definedintervals of time after administration of the substance. The substancesto be tested are suspended in a Tylose suspension and administeredintragastrally ("orally") in various doses by means of a stomach tube.The compounds according to the invention reduce the arterial bloodpressure of hypertensive rats in a clinically relevant dosage (see Table3).

Table 1: Active compound concentration at which the contraction of theaortic ring is inhibited by 50% (IC₅₀)

Isolated aortic ring from rabbits, stimulated

(a) by KCl depolarization or

(b) by noradrenaline

    ______________________________________                                                       IC.sub.50 IC.sub.50                                            Example No.    a         b                                                    ______________________________________                                        1              0.23   mg/l   >10     mg/l                                     2              0.9    mg/l   3.0     mg/l                                     3              0.23   mg/l   >10     mg/l                                     4              0.4    mg/l   5.0     mg/l                                     6              0.26   mg/l   0.36    mg/l                                     7              0.5    mg/l   1.4     mg/l                                     8              0.3    mg/l   1.6     mg/l                                     11             0.23   mg/l   0.18    mg/l                                     12             0.016  mg/l   0.4     mg/l                                     13             0.08   mg/l   0.7     mg/l                                     ______________________________________                                    

Table 2: Significant increase in vein capacity in anaesthetized cats incomparison with the reference active substance sodium nitroprusside.

    ______________________________________                                                       Dose                                                           Example No.    [mg/kg i.v.]                                                   ______________________________________                                         9             1.0                                                            11             0.1                                                            12             0.1                                                            ______________________________________                                    

Table 3: Reduction in blood pressure in hypertensive rats by 20 mm Hg(ED₂₀)

    ______________________________________                                                      ED.sub.20                                                       Example No.   [mg/kg perorally]                                               ______________________________________                                        6             1.0                                                             7             31.5                                                            8             31.5                                                            11            3.0                                                             13            3.0                                                             ______________________________________                                    

The new active compounds can be converted in a known manner into thecustomary formulations, such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, non-toxic, pharmaceutically suitable excipients or solvents. Thetherapeutically active compound should in each case be present here in aconcentration of about 0.5 to 90% by weight of the total mixture, thatis to say in amounts which are sufficient to achieve the dosage rangestated.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or excipients, if appropriate usingemulsifying agents and/or dispersing agents, and, for example, in thecase where water is used as the diluent, organic solvents can also beused as auxiliary solvents, if appropriate.

Examples of auxiliaries which may be mentioned are: water, non-toxicorganic solvents, such as paraffins (for example petroleum fractions),vegetable oils (for example groundnut/sesame oil) and alcohols (forexample: ethyl alcohol and glycerol), excipients, such as, for example,natural rock powders (for example kaolins, aluminas, talc and chalk),synthetic rock powders (for example highly disperse silicic acid andsilicates) and sugars (for example sucrose, lactose and glucose),emulsifying agents (for example polyoxyethylene fatty acid esters,polyoxyethylene fatty alcohol ethers, alkyl sulphonates, arylsulphonates), disperging agents (for example lignin-sulphite wasteliquors, methylcellulose, starch and polyvinylpyrrolidone) andlubricants (for example magnesium stearate, talc, stearic acid andsodium lauryl sulphate).

Administration is effected in the customary manner, preferably orally orparenterally, in particular perlingually or intravenously. In the caseof oral use, tablets can of course also contain, in addition to theexcipients mentioned, additives, such as sodium citrate, calciumcarbonate and dicalcium phosphate, together with various adjuvants, suchas starch, preferably potato starch, gelatine and the like. Lubricants,such as magnesium stearate, sodium lauryl sulphate and talc, canfurthermore be co-used for tablet-making. In the case of aqueoussuspensions, various flavour-improving agents or dyestuffs can be addedto the active compounds, in addition to the abovementioned auxiliaries.

In the case of parenteral use, solutions of the active compounds can beemployed, using suitable liquid excipients.

In general, it has proved advantageous, in the case of intravenousadministration, to administer amounts of about 0.001 to 1 mg/kg,preferably about 0.01 to 0.5 mg/kg of body weight, to achieve effectiveresults, and in the case of oral administration the dosage is about 0.01to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.

Nevertheless, it may at times be necessary to deviate from the amountsmentioned, and in particular to do so as a function of the body weightof the experimental animal or of the mode of administration, but also onthe basis of the animal species and its individual reaction to themedicament or the nature of its formulation and the time or interval atwhich administration takes place. Thus it can in some cases suffice tomanage with less than the abovementioned minimum amount, whilst in othercases the upper limit mentioned must be exceeded. Where relatively largeamounts are administered, it may be advisable to divide these intoseveral individual doses over the course of the day. The same dosagerange is envisaged for administration in human medicine. The abovestatements also apply here in the general sense.

Unless expressly indicated otherwise, the R_(f) values of the followingexamples were determined using thin layer chromatography precoatedplates, silica gel 60 F₂₅₄ from E. Merck, Darmstadt.

EXAMPLE 1 3-Methyl5-{6-[2-[N-benzyl-N-(2-phenoxy-1-methylethyl)amino]ethylamino]hexyl}1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate##STR28##

1.5 g (0.0035 mol) of 3-methyl 5-(6-aminohexyl)1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate areboiled under reflux with 1.1 g (0.0035 mol) ofN-benzyl-N-phenoxyisopropyl-8-chloroethylamine and 1.2 g of potassiumcarbonate in 60 ml of analytical grade dioxane for 20 hours. Thereaction mixture is cooled and concentrated on a rotary evaporator andthe residue is purified on a silica gel column(chloroform:methanol/10:1). The cooled oil is dried under a high vacuum.Fractionation gives a 540 mg yield (23% of theory) as an amorphouspowder.

R_(f) : 0.18 (10:1/CHCL₃ :CH₃ OH)

EXAMPLE 2 3-Methyl5-{6-[bis-[2-[N-benzyl-N-(2-phenoxy-1-methylethyl)amino]ethyl]amino]hexyl}1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate##STR29##

From the reaction mixture obtained in the preparation of Example 1, 490mg of the compound of Example 2 are obtained in the form of an amorphouspowder during fractionation.

R_(f) : 0.42 (10:1/CHCl₃ :CH₃ OH)

EXAMPLE 3 3-Isopropyl5-{2-[2-[N-benzyl-N-(2-phenoxy-1-methylethyl)amino]ethylamino]ethyl}1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate##STR30##

Yield: 27% of theory

Melting point: amorphous

R_(f) : 0.42 (10:1/CHCl₃ :CH₃ OH)

EXAMPLE 4 3-Isopropyl5-(2-[bis-[2-[N-benzyl-N-(2-phenoxy-1-methylethyl)amino]ethyl]amino]ethyl}1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate##STR31##

Yield: 26% of theory

Melting point: amorphous

R_(f) : 0.8 (10:1/CHCl₃ :CH₃ OH)

EXAMPLE 5 3-Methyl5-[6-(1,3,4,6,7,11b-hexahydro-8,9-dimethoxy-2H-benzo[a]quinolizin-2-yl-amino)hexyl]1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate##STR32##

1.3 g (0.005 mol) of1,3,4,6,7,11b-hexahydro-8,9-dimethoxy-benzo[a]quinolizin-2-one aredissolved in 30 ml of methanol and the pH is brought to 6 withmethanolic hydrochloric acid. 2.1 g (0.005 mol) of 3-methyl5-(6-aminohexyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate inmethanol are added to this solution and the mixture is stirred with a 3Å molecular sieve at room temperature for 2.5 hours. 320 mg of sodiumcyanoborohydride are then added in portions and the mixture is stirredat room temperature for 20 hours. The reaction mixture is filtered andthe filtrate is acidified and concentrated on a rotary evaporator.Methylene chloride is added to the residue, the mixture is renderedalkaline with dilute sodium hydroxide solution and the organic phase iswashed with water, dried over sodium sulphate, filtered and concentratedin vacuo. The residue is purified on a silica gel column(chloroform:methanol:triethylamine/10:0.5:0.25). The product thusobtained is then dried under a high vacuum.

Yield: 1.6 g (48% of theory), amorphous.

R_(f) : 0.76 (1:1/CHCl₃ :CH₃ OH)

The following compounds are prepared analogously to Example 5:

EXAMPLE 6 3-Methyl5-12-(1,3,4,6,7,11b-hexahydro-8,9-dimethoxy-2H-benzo[a]quinolizin-2-yl-amino)ethyl]1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate##STR33##

Yield: 48% of theory

Melting point: amorphous.

R_(f) : 0.3 (20:1:0.5/CHCl₃ :CH₃ OH:(C₂ H₅)₃ N)

EXAMPLE 7 3-Isopropyl5-[3-(1,3,4,6,7,11b-hexahydro-8,9-dimethoxy-2H-benzo[a]quinolizin-2-yl-amino)propyl]1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate##STR34##

Yield: 47% of theory

Melting point: amorphous.

R_(f) : 0.76(1:1/CHCl₃ :CH₃ OH)

EXAMPLE 8 3-Isopropyl5-[2-(1,3,4,6,7,11b-hexahydro-8,9-dimethoxy-2H-benzo[a]quinolizin-2-yl-amino)ethyl]1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate##STR35##

Yield: 47% of theory

Melting point: amorphous.

R_(f) : 0.33 (20:1:0.5/CHCl₃ :CH₃ OH:(C₂ H₅)₃ N)

EXAMPLE 9 3-Isopropyl5-[2-(1,3,4,6,7,11b-hexahydro-9-methoxy-2H-benzo[a]quinolizin-2-yl)amino]ethyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate##STR36##

Yield: 27.1% of theory

R_(f) : 0.14 (CHCl₃ :CH₃ OH:NH₃ /20:1:0.05)

EXAMPLE 10 3-Methyl5-[6-(benzodioxan-2-yl-methylamino)hexyl]1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate##STR37## Process A

430 mg (0.001 mol) of 3-methyl 5-(6-aminohexyl)1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate areboiled under reflux with 230 mg (0.001 mol) of2-bromomethyl-1,4-benzodioxane and 200 mg of K₂ CO₃ in 30 ml ofanalytical grade dioxane for 15 hours. The reaction mixture is cooledand concentrated on a rotary evaporator. Sodium bicarbonate solution isadded to the residue and the mixture is extracted twice with 50 ml ofmethylene chloride each time. The combined organic phases are dried oversodium sulphate, filtered and concentrated in vacuo. The residue ispurified on a silica gel column (ethyl acetate:methanol/4:1). Theproduct thus obtained is then dried under a high vacuum.

Yield: 310 mg (53% of theory)

Melting point: amorphous.

R_(f) :0.43 (4:1/ethyl acetate:CH₃ OH)

Process B

82 mg (0.0005 mol) of 2-formyl-1,4-benzodioxane are dissolved in 3 ml ofmethanol and the pH is brought to 6 with methanolic hydrochloric acid. Asolution of 200 mg (0.005 mol) of 3-methyl5-(6-aminohexyl)1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylateand 10 ml of methanol is added and the reaction mixture is stirred witha 3 Å molecular sieve at room temperature for 2.5 hours. 32 mg of sodiumcyanoborohydride are then added in portions and the mixture is stirredfor 20 hours. After filtration and concentration on a rotary evaporator,water and methylene chloride are added to the residue. The organic phaseis separated off, dried with sodium sulphate and concentrated. Theresidue is purified over a silica gel column (ethyl acetate). Theproduct thus obtained is dried under a high vacuum.

Yield: 158 mg (57% of theory)

Melting point: amorphous.

R_(f) : 0.49 (4:1/ethyl acetate:CH₃ OH)

The following compounds are prepared analogously to Example 10:

EXAMPLE 11 3-Methyl5-{2-[N-(1,4-benzodioxan-2-yl-methyl)-N-methylamino]ethyl}1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate##STR38##

Melting point: amorphous.

Yield: 21% of theory

R_(f) : 0.72 (ethyl acetate)

EXAMPLE 12 3-Isopropyl5-[2-(1,4-benzodioxan-2-yl-methylamino)ethyl]1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate##STR39##

Melting point: amorphous

Yield: 45% of theory

R_(f) : 0.41 (ethyl acetate)

EXAMPLE 13 3-Methyl5-[2-(1,4-benzodioxan-2-yl-methylamino)ethyl]1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate##STR40##

Yield: 64% of theory

Melting point: amorphous.

R_(f) : 0.33 (ethyl acetate)

EXAMPLE 143-Isopropyl-5-[3-(1,4-benzodioxan-2-yl-methylamino)propyl]1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate##STR41##

Yield: 34% of theory

Melting point: amorphous.

R_(f) : 0.72 (4:1/ethyl acetate:CH₃ OH)

EXAMPLE 15 3-Methyl5-{2-[2-(1,4-benzodioxan-2-yl-methyl)imidazol-1-yl]ethyl}1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate##STR42##

180 mg (0.006 mol) of sodium hydroxide and 15 ml of analytical gradedimethylformamide are cooled to 0° C. under nitrogen and 620 mg (0.0025mol are added. The mixture is stirred at room temperature for 0.5 hourand a solution of 1.1 g (0.0025 mol) of 3-methyl 5-(2-bromoethyl)1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate and20 ml of analytical grade dimethylformamide is then added dropwise at 0°C. After a further 30 minutes at room temperature, H₂ O is addeddropwise to the reaction mixture, with cooling, and the mixture isextracted 3 times with ethyl acetate. The combined organic phases arewashed 3 times with H₂ O, dried over sodium sulphate and concentrated ona Rotavapor. The residue is purified over a silica gel column (ethylacetate). The product thus obtained is dried under a high vacuum.

Yield: 33% of theory

Melting point: amorphous.

R_(f) : 0.15 (ethyl acetate)

The following compounds are prepared analogously to Example 15:

EXAMPLE 16 3-Methyl5-{6-[2-(1,4-benzodioxan-2-yl-methyl)imidazol-1-yl]hexyl}1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate##STR43##

Yield: 42% of theory

Melting point: amorphous.

R_(f) : 0.15 (ethyl acetate)

EXAMPLE 173-Methyl-5-{6-[2-(1,4-benzodioxan-2-yl-methyl)imidazol-1-yl]hexyl}1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)pyridine-3,5-dicarboxylate##STR44##

Yield: 46% of theory

Melting point: amorphous.

R_(f) : 0.16 (ethyl acetate)

We claim:
 1. An aminoalkyl ester of a dihydropyridinedicarboxylic acid of the formula ##STR45## in which R¹ is phenyl, the phenyl ring being optionally substituted by 1 or 2 identical or different substituents from the group consisting of chlorine, trifluoromethyl, nitro and cyano,R² is a straight-chain or branched hydrocarbon radical which has up to 7 carbon atoms and is optionally interrupted in the chain by an oxygen atom and said hydrocarbon radical is optionally substituted by fluorine and cyano, X is a number from 2 to 6, and R⁶ represents a radical of the formula ##STR46##
 2. A compound or salt according to claim 1, in whichR¹ is phenyl optionally substituted by 1 or 2 identical or different substituents selected from the group consisting of chlorine, trifluoromethyl, nitro and cyano, R² is a straight-chain or branched hydrocarbon radical which has up to 7 carbon atoms and is optionally interrupted in the chain by an oxygen atom and said hydrocarbon radical is optionally substituted by fluorine and cyano, and R⁶ is ##STR47##
 3. A compound according to claim 1, wherein such compound is 3-methyl 5-[6-(benzodioxan-2-yl-methylamino)hexyl]1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate of the formula ##STR48##
 4. A compound according to claim 1, wherein such compound is 3-methyl 5-{2-[N-(1,4-benzodioxan-2-yl-methyl)-N-methyl-amino]ethyl}1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate of the formula ##STR49##
 5. A compound according to claim 1, wherein such compound is 3-isopropyl 5-[2-(1,4-benzodioxan-2-yl-methylamino)ethyl]1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate of the formula ##STR50##
 6. A compound according to claim 1, wherein such compound is 3-methyl 5-[2-(1,4-benzodioxan-2-yl-methylamino)ethyl]1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate of the formula ##STR51##
 7. A compound according to claim 1, wherein such compound is 3-isopropyl-5-[3-(1,4-benzodioxan-2-yl-methylamino)propyl]1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate of the formula ##STR52##
 8. A compound according to claim 1, wherein such compound is 3-methyl 5-{2-[2-(1,4-benzodioxan-2-yl-methyl)imidazol-1-yl]ethyl}1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate of the formula ##STR53##
 9. A compound according to claim 1, wherein such compound 3-methyl 5-{6-[2-(1,4-benzodioxan-2-yl-methyl)imidazol-1-yl]hexyl}1,4-dihydro-2,6-dimethyl-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate of the formula ##STR54##
 10. A compound according to claim 1, wherein such compound 3-methyl-5-{6-[2-(1,4-benzodioxan-2-yl-methyl)-imidazol-1-yl]hexyl}1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethyl-phenyl)pyridine-3,5-dicarboxylate of the formula ##STR55##
 11. A circulation-active composition comprising a circulation-active effective amount of a compound or salt according to claim 1 and a physiologically acceptable diluent.
 12. A unit dose of a composition according to claim 11 in the form of a tablet, capsule or ampule.
 13. A method of improving the circulation of a patient in need thereof which comprises administering to said patient a circulation-active effective amount of a compound or salt according to claim
 1. 14. The method according to claim 13, wherein said compound is3-methyl 5-[6-(benzodioxan-2-yl-methylamino)hexyl]1,4-dihydro-2,6 -dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate, 3-methyl 5-{2-[N-(1,4-benzodioxan-2-yl-methyl)-N-methylamino]ethyl}1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate, 3-isopropyl 3-[2-(1,4-benzodioxan-2-yl-methylamino)ethyl]1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate, 3-methyl 5-[2-(1,4-benzodioxan-2-yl-methylamino)ethyl]1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate, 3-isopropyl-5-[3-(1,4-benzodioxan-2-yl-methylamino)propyl]1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate. 3-methyl 5-{2-[2-(1,4-benzodioxan-2-yl-methyl)imidazol-1-yl]ethyl}1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate, 3-methyl 5-{-[2-(1,4-benzodioxan-2-yl-methyl)imidazol-1yl]hexyl}1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate, or 3-methyl-5-{6-[2-(1,4-benzodioxan-2-yl-methyl)imidazol-1-yl)hexyl}1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)pyridine-3,5-dicarboxylate. 